Introduction
Corneal collagen crosslinking (CXL) is a minimally invasive process that’s presently presupposed to arrest the development of corneal ectatic circumstances. CXL induces crosslinks within the stromal collagen of the cornea.
These ectatic modifications are usually marked by corneal thinning and a rise within the anterior and/or posterior curvatures of the cornea, and infrequently result in excessive ranges of myopia and astigmatism. The most typical type of ectasia is keratoconus and fewer usually ectasia is seen after laser imaginative and prescient correction reminiscent of LASIK.
Background
Cross-linking of collagen refers back to the capacity of collagen fibrils to kind robust chemical bonds with adjoining fibrils. Within the cornea, collagen cross-linking happens naturally with growing old because of an oxidative deamination response that takes place inside the finish chains of the collagen. It has been hypothesized that this pure cross-linkage of collagen explains why keratectasia (corneal ectasia) usually progresses most quickly in adolescence or early maturity however tends to stabilize in sufferers after middle-age.
Along with the cross-linking that happens generally with corneal maturation, there are a number of different pathways that may result in crosslinkage. Glycation refers to a response seen predominantly in diabetics that may result in the formation of further bonds between collagen. Within the pathway most related to this matter, oxidation has been proven to have the ability to set off corneal crosslinkage by way of the discharge of oxygen free radicals.
The bases for the presently employed corneal collagen cross-linking strategies had been developed in Europe by researchers on the College of Dresden within the late Nineties. UV gentle was used to induce collagen cross-linking in riboflavin soaked porcine and rabbit corneas through the oxidation pathway. The resultant corneas had been proven to be stiffer and extra proof against enzymatic digestion. The investigation additionally proved that handled corneas contained larger molecular weight polymers of collagen because of fibril crosslinking. Security research confirmed that the endothelium was not broken by the remedy if correct UV irradiance was maintained and if the corneal thickness exceeded 400 microns.[1]
Human research of UV-induced corneal cross-linking started in 2003 in Dresden, and early outcomes had been promising. The preliminary pilot research enrolled 16 sufferers with quickly progressing keratoconus and all the sufferers stopped progressing after remedy. Moreover, 70% had flattening of their steep anterior corneal curvatures (decreases in common and most keratometric values), and 65% had an enchancment in visible acuity. There have been no reported issues. [2]
In late 2011, orphan drug standing was awarded by the FDA to Avedro for its formulation of riboflavin ophthalmic resolution for use together with the corporate’s explicit UVA irradiation system. Corneal collagen cross-linking utilizing riboflavin and UV acquired FDA approval on April 18, 2016.
In 2015, a cochrane systemic overview analysing CXL for treating keratoconus revealed that the proof for using CXL within the administration of keratoconus is proscribed due the dearth of correctly performed Randomized Managed Trials.
Fundamental Ideas
The principle elements of CXL are a photosensitizer, an efficient and protected gentle supply, and the ensuing photochemical response.
Riboflavin
A photosensitizer is a molecule that absorbs gentle vitality and produces a chemical change in one other molecule.
In CXL, Riboflavin is used because the photosensitizer. It’s protected systemically and may be adequately absorbed by the corneal stroma topically. It has an absorption peak at 370 nm.[3]
UV Mild
Because the absorption peak of riboflavin was famous to be 370 nm, UV-A lightweight was discovered to be ultimate for CXL, whereas on the similar time defending the opposite ocular buildings. The whole fluence required was discovered to be 5.4J/cm2.
The Bunsen Roscoe legislation states that the photochemical impact must be related if the full fluence stays fixed. Primarily based on this, varied protocols have been devised with totally different combos of the depth and period of UV-A publicity.[4] Nevertheless, it has been famous that CXL fails to be efficient as soon as the vitality depth exceeds 45mW/cm2.
Photochemical Response
As soon as uncovered to UV-A lightweight, the riboflavin generates Reactive oxygen species, which induce the formation of covalent bonds each between collagen molecules and between collagen molecules and proteoglycans.[5]
Oxygen
Latest research point out that the presence of oxygen is crucial for efficient CXL.[5]
Affected person Choice
Indications
The first function of cross-linking is to halt the development of ectasia. Likewise, the perfect candidate for this remedy is a person with a progressive ectatic illness of the cornea. The most typical indication is keratoconus. Different ailments which may be candidates embrace Pellucid Marginal Degeneration, Terrien Marginal Degeneration, and post-refractive surgical procedure (reminiscent of LASIK, PRK, or Radial Keratotomy) ectasia. There presently are not any definitive standards for development, however parameters to contemplate are change in refraction (together with astigmatism), uncorrected visible acuity, finest corrected visible acuity, and corneal form (topography and tomography).
Contraindications
Corneal thickness of lower than 400 microns is a contraindication to the usual remedy protocol
Prior herpetic an infection is a contraindication as a result of it could lead to viral reactivation
Concurrent an infection
Extreme corneal scarring or opacification
Historical past of poor epithelial wound therapeutic
Extreme ocular floor illness (ex. dry eye)
Autoimmune issues
Surgical Method
The usual remedy protocol, known as the Dresden protocol[2], was formulated by Wollensak et al. for corneas with minimal thickness of 400µm, and is as follows:
Instill topical anesthetic drops within the eye
Debride the central 7-9mm of corneal epithelium
Instill 0.1% riboflavin 5-phosphate drops and 20% dextran resolution each 5 minutes for half-hour
Publicity to UVA (370nm, 3mw/cm 2 ) for half-hour whereas persevering with instilling the above drops each 5minutes.
) for half-hour whereas persevering with instilling the above drops each 5minutes. On the finish of the process, apply topical antibiotics and mushy BCL with good oxygen permeability.
Within the video proven, anesthetic drops are given, then the speculum is positioned and the epithelium is eliminated. Subsequent, drops of riboflavin are administered, adopted by UV publicity.
Variations in Surgical Method
Variations in Riboflavin
Supply
Epithelium-off methodology
Because the corneal epithelium presents a barrier to the diffusion of riboflavin to the stroma, the epithelium is manually debrided to allow higher penetration. The epithelium-off methodology is the usual methodology and stays the simplest.[4]
Epithelium-on methodology / Trans-epithelial methodology
Varied strategies have been tried to keep away from epithelium debridement. These embrace using pharmacological brokers to loosen the intraepithelial junctions, the creation of intrastromal pockets for direct introduction of riboflavin, and iontophoresis.
Regardless that debridement induced issues like postoperative ache and corneal haze are prevented, research to this point have demonstrated decrease effectiveness of CXL on this methodology.[5]
Osmolarity
Hypo-osmolar riboflavin is utilized in skinny corneas with a thickness between 400 and 320 µm when the Dresden protocol is precluded.[6]
Variations in UV Publicity
Remedy Time – Accelerated CXL
A number of protocols have been tried to cut back the remedy time by growing the depth of UV publicity. Research have proven {that a} center path with an irradiation dose of 10mW/cm2 for 9 minutes has a greater therapeutic and security profile than larger irradiation doses for shorter intervals.[5]
Positioning
Historically, CXL is carried out within the supine place within the operation room. There are few latest studies on the nuances of crosslinking carried out on the slit lamp by Hafezi et al. [7]
Results and Security of CXL
Crosslinking impact are seen extra within the anterior cornea, as riboflavin focus reduces with growing depth. IOP measurements usually are not affected considerably submit CXL.
The debrided epithelium is changed in 3-4 days. Limbal stem cells usually are not broken by CXL, as riboflavin is stored away by the remaining peripheral epithelium.
CXL causes apoptosis of keratocytes within the anterior stroma, and within the following weeks, new keratocytes are discovered migrating from the periphery to the middle. Because the stroma heals, collagen compaction, and a hyperdense extracellular matrix are seen.
No endothelial harm is brought on by CXL when appropriately carried out. The subepithelial basal nerve plexus is obliterated by this process; nonetheless, it begins to regenerate after seven days.
Therefore, CXL alters regular corneal construction and cellularity not less than for 36 months.[6]
Functions and Outcomes
Controversies exist as to when to carry out CXL. Given the pure historical past of the illness, it’s prudent to carry out CXL when development is documented. It is also crucial to advise keratoconus sufferers to cease eye rubbing and to keep away from particular sleeping positions as these components seem to play a serious position within the development of keratoconus.
For additional visible rehabilitation together with stabilization of keratoconus, totally different approaches to combining CXL with refractive surgical procedure, CXL Plus, have been described. Personalized CXL relying on the stage of keratoconus and refractive error, CXL together with photorefractive keratectomy and CXL with Intracorneal stromal rings or phakic IOL are a few of the strategies.[4][8]
Being a uncommon ectatic dysfunction often involving the inferior peripheral cornea, CXL has been tried in these eyes by decentering the main target of irradiation to contain the pathological web site. Studies counsel enchancment in visible acuity, keratometry, and astigmatism parameters. Regardless that long-term stability is but to be studied, within the absence of significant issues, CXL does purchase time to postpone additional tectonic surgical interventions.[3][9]
CXL for post-Lasik ectasia has been discovered to stabilize or enhance visible acuity and keratometric parameters. The ‘Athens protocol’ described by Kanellopoulos et al. combines CXL with PRK for managing submit Lasik ectasia. Lasik Xtra is a brand new process for Lasik adopted by modified CXL to forestall post-Lasik ectasia. Nevertheless there is no such thing as a proof concerning the profit, security and stability of such strategy. [3][8][9]
PhotoActivated Chromophore for infectious Keratitis – corneal collagen crosslinking
Strengthening of the cornea by CXL and the microbicidal exercise of UV irradiation has been utilized efficiently within the administration of keratitis with stromal soften. Because the consistency of outcomes is but to be demonstrated, presently CXL is taken into account solely within the circumstances resistant to straightforward antimicrobial remedy.[8]
Research have proven that CXL causes a discount in corneal edema and thickness with enchancment in visible acuity in sufferers with bullous keratopathy because of totally different causes. Nevertheless, these modifications final for less than about six months and because of this transient impact, CXL could solely have a palliative position, if in any respect, for now.[9]
Research and Trials
[10] C.G. Carus College Hospital, Dresden, Germany Research
The power of this research is its giant pattern dimension at 1 12 months. The weaknesses are its poor definition of the illness being handled (a serious flaw) and poor pattern dimension after 1 12 months.
Enrolled 480 eyes of 272 sufferers
Definition of development: ≥1D change in keratometry worth over 1 12 months,or, Want for a brand new contact lens match ≥1 in 2 years,or,”Patient reports of decreasing visual acuity”
241 eyes with ≥6 months knowledge post-CXL, 33 eyes with ≥3 years knowledge post-CXL
Important enchancment in BCVA at 1 12 months (-0.08 logMAR BCVA) and three yrs (-0.15 logMAR BCVA)
Important lower in imply keratometry in 1st 12 months (-2.68D)
53% of eyes with ≥1 traces enchancment BCVA 1st 12 months; One other 20% steady in 1st 12 months
87% of eyes had been steady or improved at 3 yrs (Nevertheless, very low numbers had been included on this evaluation so conclusions have to be drawn rigorously)
[11] Siena Eye Cross Research
The power of this research can be its pattern dimension at 1 12 months. Much like the Dresden research, its interpretation and software to a wider set of sufferers is proscribed by a poorly outlined affected person inhabitants. There may be additionally a small pattern dimension at 4 years.
Enrolled 363 eyes with progressive keratoconus
Definition of development: Solely states that it was outlined “clinically and instrumentally within 6 months”
44 eyes with ≥48 months of information post-CXL
Important enchancment in manifest spherical equal at 1 12 months (+1.62D) and 4yrs (+1.87D)
Important discount of imply keratometry values by 1 12 months (-1.96D) and 4 years (-2.26D)
No important change in pachymetry
No important change in UCVA/BCVA
No important change in cylinder
[12]
Australian Research
This ongoing research has the perfect printed research design and definition of development up to now. The researchers are taking a look at sufferers with clearly outlined progressive keratoconus and can comply with them for five years. The three-year knowledge was printed in April 2014 and is described beneath. [13]
Definition of development (throughout 12 months): Enhance in cylinder on manifest refraction by ≥1D; or Enhance in steepest keratometry worth (on Sim Okay or Handbook) by ≥1D; or Lower in again optic zone radius of best-fitting contact lens by >0.1mm
Strategies:
Eligible eyes randomized independently to both cross-linking or management group
Major end result measure: Most simulated keratometry worth (Kmax)
Secondary end result measures: Uncorrected visible acuity (UCVA), Greatest-spectacle corrected visible acuity (BSCVA); spherical and cylindrical error on manifest refraction, spherical equal, minimal simulated keratometry worth (Kmin), corneal thickness at thinnest level; endothelial cell density; and intraocular stress
Assessments had been carried out at 3,6,12,24, and 36 months.
Remedy: Dresden Protocol (Epi-off): Riboflavin 0.1% drops utilized (after epithelial elimination with a 57 Beaver blade) each 1-3 minutes x quarter-hour and continued each 1-3 minutes as wanted over the 30 minute UV publicity interval. UV-X machine delivered UV-A 370nm at 3.0mW/cm2 by way of a 9mm aperture at a distance of 50mm from the corneal apex.
Management eyes didn’t obtain sham. At 6 months compassionate remedy with CXL was allowed in management eyes, however this then excluded additional affected person inclusion within the research. Subsequently, remaining outcomes are evaluating solely handled vs untreated eyes.
Recruitment resulted in 2009 with 50 management eyes and 50 remedy eyes.
Outcomes:
Three 12 months research studies on 46 handled eyes and 49 management eyes. Out of the 49 management eyes 12 underwent CXL and 5 had corneal transplantation. 5 handled and 4 management withdrew for private causes.The outcomes usually are not described by an intention to deal with evaluation (ITT), so the info after drop-out or crossover on the research sufferers will not be included within the reported outcomes.
Major end result outcomes: Important distinction in Kmax in any respect time factors. Handled: Common Kmax flattening was -1.03 +/-0.19D. 6/46 eyes (13%) flattened by ≥ 2.0 D. 1 eye steepened by ≥ 2.0 D. Management: Common Kmax steepening was +1.75 +/- 0.38 D. No eyes flattened by ≥ 2.0 D. 19/49 eyes (39%) steepened by ≥ 2.0 D. A damaging correlation reported between baseline Kmax and alter in Kmax at 36 months. Biggest enchancment with eyes having a baseline Kmax ≥ 54.0 D in remedy group. A damaging correlation reported between affected person’s age at enrollment and alter in Kmax in management group.
Secondary end result outcomes: UCVA: Improved in remedy group in comparison with baseline at 12, 24, 36 months (P < 0.001). Worsened in management group in comparison with baseline at 36 months (P<0.001). - BSCVA: Improved in remedy group compated to basline at 12, 24, and 36 months (P<0.007). No important change in management group in comparison with baseline at 36 months. No important distinction between handled and management at any time level. Manifest spherical refraction: No important distinction at any time level. Manifest cylindrical error: No important change from baseline in remedy group. Corneal thickness at thinnest level on ultrasound: No important change in remedy group at any time level. Decreased in management group at 36 months (p=0.029) . Corneal thickness at thinnest level on Orbscan: Remedy group confirmed important lower most marked at 3 months of -93.00 +/- 7.98 microns (p<0.001). This reversed over the follow-up interval of 36 months to -19.52 +/- 5.06 microns. Management group confirmed progressive lower at 12, 24, 36 months (p<0.001). Intraocular pressure: No significant change using Tonopen in either group. Using Goldmann, significant decrease at 36 months in both groups, but no significant difference between groups. Adverse Events: Keratitis and corneal edema: 1 case. Authors attributed to premature resumption of RGP wear. Did not adversely affect outcome but did cause scar. Keratitis and iritis: 1 case. Started two days after treatment and presumed to be microbial keratitis. Resolved on ofloxacin and fluorometholone acetate 0.1%. Culture negative. Peripheral corneal neovascularization: 1 case. Noted at 36 months and attributed to acne rosacea and not CXL. Haze: All patients had some degree of haze and this resolved with time Conclusions: The authors of this study declared in their three year report the following pertinent statments : "The findings of this study suggest that CXL should continue to be considered as a treatment option for patients with progressive keratoconus" "Despite the growing body of literature and continuing efforts to optimize the treatment protocol, there remains a lack of randomized controlled studies with longer-term follow-up to support the widespread clinical use of CXL for keratoconus" US FDA Phase III trials AVEDRO: The unique strengths of the completed and reported Avedro studies, NCT00674661 and NCT00647699, were an actual sham control group. However, this was also a major design shortcoming which limited the interpretation of the study data because the sham patients were allowed to seek treatment as early as 3 months into the study (see below). This time point of crossover was changed at the request of FDA. The definition of progressive disease was not as rigorous as in the Australian study but was more clearly defined than most other reported RCCTs. 11 U.S. sites Keratoconus: 204 eyes enrolled Ectasia: 178 eyes enrolled A single investigator, Dr. Peter Hersh, reported his results and published in 2011, but the full trial group results have not since been reported. Here is what Dr. Hersh reported:[14] Enrolled 112 eyes with progressive ectasia (77 eyes with keratoconus, 35 eyes with post-LASIK ectasia) Definition of progression (all over 24 months-- twice the amount of time as study above): Decrease sphere by ≥0.5D*, or, Decrease cylinder by ≥1D, Increase steepest keratometry value by ≥1D Note: While ≥0.5D change in sphere over 2 years was considered disease progression, baseline refractions for patients were considered "stable" if they were within 0.75D on two consecutive measurements. Also, this study enrolled patients starting at age 14, complicating the interpretation of disease progression vs progressive myopia in cases of small changes in refraction (just >0.5D), particularly in adolescents.
Randomized eyes with progressive illness to both remedy (49 keratoconus / 22 ectasia) or sham (28 keratoconus /13 ectasia)
The sham group was allowed to cross-over into remedy by three months, limiting the usefulness of this true management group nearly totally, since many of the enhancements within the handled group weren’t seen till after 3 months. There will likely be no knowledge for comparability at 1 12 months. In impact, these research are solely observational research after the three month time level.
Additionally checked out a fellow eye “control” group, a gaggle of eyes failing to fulfill the definitions of progressive illness. Since these eyes wouldn’t have progressive illness, they’re dissimilar to handled eyes at baseline and cannot function a management.
Important enchancment in most, common, and minimal keratometry values (+1.7D, 1.1D, 0.9D respectively) within the remedy group at 1 12 months
Important enchancment in UCVA and BCVA at 1 12 months in remedy group (-0.07 and -0.12). Nevertheless, there was additionally important enchancment within the sham group UCVA at 3 months (the ultimate measurement for this cohort) by -0.08. This demonstrates how the research design limits our interpretation of the info. Our solely comparability time factors present the untreated eyes improved extra within the main end result, visible acuity, then the handled eyes.
No important change in spherical equal or cylinder within the remedy group at 1 12 months
Sham group additionally had no change in CDVA, spherical equal, cylinder, or Okay values at its endpoint (3 months)
Problems
Short-term stromal edema (as much as 70%), short-term haze (as much as 100%), and everlasting haze (as much as 10%)
Corneal scarring and sterile infiltrates [15] [16]
Infectious keratitis: Bacterial/protozoan/herpetic [17] [18] [19]
Diffuse lamellar keratitis (DLK) in a post-LASIK affected person[20]
Particular Conditions
Paediatric Keratoconus
Keratoconus identified in kids is often related to an unfavorable prognosis and an elevated want for a corneal transplant. Therefore, on this age group, CXL is suggested instantly with out the necessity for documenting development, because the illness tends to be extra aggressive.
The Siena Paediatrics CXL research was performed on 152 keratoconus sufferers between 10 and 18 years of age. It demonstrated speedy purposeful enchancment and higher long-term stability no matter preliminary corneal thickness in 80% of sufferers. As anticipated, sufferers with thicker corneas did higher than the sufferers with thinner corneas.[4][9]
Skinny Cornea
In line with the Dresden protocol, for protected crosslinking of the cornea, the minimal corneal thickness required is 400 µm. Nevertheless, as many circumstances of keratoconus have skinny corneas, totally different modifications have been tried to cross-link these eyes safely.
In corneas with a minimal thickness of 350 µm, hypo-osmolar riboflavin resolution has been used to trigger corneal swelling. The CXL impact will not be compromised because the anterior stroma stays the identical whereas it’s the posterior corneal stroma that swells significantly, in flip additionally defending the endothelium.
Previous to the arrival of hypo-osmolar riboflavin, different strategies like lowering the UV irradiation depth and never debriding the central epithelium had been tried; nonetheless, CXL effectiveness was compromised.
Utilizing larger focus riboflavin of 0.2% has been tried to extend the UV absorption within the anterior stroma and therefore shield the endothelium.[6]
Keratectasia in Being pregnant
Being pregnant is related to hormonal modifications that may negatively affect corneal biomechanics. Therefore it’s advisable to observe pregnant sufferers with keratoconus or latest refractive surgical procedure intently. CXL is prevented throughout being pregnant, maintaining in thoughts the potential of issues which will require systemic remedy or further procedures. If wanted, CXL could also be achieved after supply. Regardless of CXL being achieved, these sufferers have to be knowledgeable that the ectasia could progress throughout subsequent being pregnant because of the hormonal modifications. For a similar motive, it might be prudent for these sufferers to keep away from hormonal contraception strategies.[9]
Advances
Pulsed CXL
It has been postulated that pulsed supply of UVA radiation, would allow higher oxygen diffusion into the stroma. As oxygen has a necessary position within the photochemical response, the presence of extra oxygen would translate to higher impact. Additional research are required to find out the best pulsing strategy.[8]
Tailored Fluence
UV-A fluence delivered in all circumstances no matter the protocol has remained fixed at 5.4J/cm2. Hafezi and Kling have put ahead the idea of tailored fluence the place the vitality delivered is custom-made for the cornea. Whereas this may occasionally enhance the security profile of CXL particularly in skinny corneas, it stays to be validated.[8]
LASIK XTRA
Lasik Xtra is a process the place CXL is mixed with Lasik. After elevating the flap and performing laser ablation, larger focus riboflavin (0.25%) is utilized to the stromal mattress for about 90 seconds. After this, the interface is washed, and flap changed. Then half fluence high-intensity UV irradiation is carried out. Outcomes up to now have proven promise, with higher refractive stability and diminished incidence of submit Lasik regression and ectasia.[8]
Photorefractive Intrastromal CXL
Excessive‑Fluence CXL is being tried in sufferers with low myopia to induce subsequent flattening and refractive correction.[8]
Scleral CXL in Axial Myopia
Progressive myopia is accompanied by scleral thinning and elongation. In vitro research are being performed to crosslink the sclera and therefore stall the development.[8]
Different CXL strategies
Photochemical CXL with different brokers like Rose Bengal dye and derivatives of photosynthetic brokers like chlorophyll is being studied. Utilizing a contact lens to extend the corneal thickness in skinny corneas, throughout crosslinking has been steered and termed CACXL – contact lens assisted cross linking. Purely chemical CXL, utilizing molecules like Genipin and β-nitro alcohols, is being investigated.[3]
Abstract
References
↑ P T Ashwin, P J McDonnell. Collagen cross-linkage: a complete overview and instructions for future analysis. Br J Ophthalmol 2010;94:965e970. 2.0 2.1 Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the remedy of keratoconus.Am J Ophthalmol. 2003 Could;135(5):620-7. 3.0 3.1 3.2 3.3 Sorkin N, Varssano D. Corneal Collagen Crosslinking: A Systematic Overview. OPH. 2014;232(1):10-27. doi:10.1159/000357979 4.0 4.1 4.2 4.3 Randleman JB, Khandelwal SS, Hafezi F. Corneal cross-linking. Surv Ophthalmol. 2015;60(6):509-523. doi:10.1016/j.survophthal.2015.04.002 5.0 5.1 5.2 5.3 Subasinghe SK, Ogbuehi KC, Dias GJ. Present views on corneal collagen crosslinking (CXL). Graefes Arch Clin Exp Ophthalmol. 2018;256(8):1363-1384. doi:10.1007/s00417-018-3966-0 6.0 6.1 6.2 Raiskup F, Spoerl E. Corneal crosslinking with riboflavin and ultraviolet A. I. Ideas. Ocul Surf. 2013;11(2):65-74. doi:10.1016/j.jtos.2013.01.002 ↑ Salmon B, Richoz O, Tabibian D, Kling S, Wuarin R, Hafezi F. CXL on the Slit Lamp: No Clinically Related Modifications in Corneal Riboflavin Distribution Throughout Upright UV Irradiation. J Refract Surg. 2017;33(4):281. 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 Sachdev GS, Sachdev M. Latest advances in corneal collagen cross-linking. Indian Journal of Ophthalmology. 2017;65(9):787. doi:10.4103/ijo.IJO_648_17 9.0 9.1 9.2 9.3 9.4 Raiskup F, Spoerl E. Corneal crosslinking with riboflavin and ultraviolet A. Half II. Scientific indications and outcomes. Ocul Surf. 2013;11(2):93-108. doi:10.1016/j.jtos.2013.01.003 ↑ Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A lightweight in keratoconus: long-term outcomes. J Cataract Refract Surg. 2008 Could;34(5):796-801. ↑ Caporossi A, Mazzotta C, Baiocchi S, Caporossi T.Lengthy-term outcomes of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross research. Am J Ophthalmol. 2010 Apr;149(4):585-93. Epub 2010 Feb 6. ↑ Wittig-Silva, C; Whiting M, Lamoureux E, Lindsay RG, Sullivan LJ, Snibson GR. A Randomized Managed Trial of Corneal Collagen Cross-linking in Progressive Keratoconus: Preliminary Outcomes. Journal of Refractive Surgical procedure. 2008 (24): S720 – S725. ↑ Wittig-Silva C et al. A Randomized, Managed Trial of Corneal Collagen Cross-linking in Progressive Keratoconus: Three-Yr Outcomes. Ophthalmology. 2014. Quantity 121 (4); 812-821. ↑ Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: One-year outcomes. J Cataract Refract Surgical procedure. 2011 (37): 149-160 ↑ Mazzotta C, Balestrazzi A, Baiocchi S, et al. Stromal haze after mixed riboflavineUVA corneal collagen cross-linking in keratoconus: in vivo confocal microscopic analysis. Clin Experiment Ophthalmol 2007;35:580e2. ↑ Koller T, Mrochen M, Seiler T. Complication and failure charges after corneal crosslinking. J Cataract Refract Surg. 2009 Aug;35(8):1358-62. ↑ Pollhammer M, Cursiefen C. Bacterial keratitis early after corneal crosslinking with riboflavin and ultraviolet-A. J Cataract Refract Surg 2009;35:588e9. ↑ Rama P, Di Matteo F, Matuska S, et al. Acanthamoeba keratitis with perforation after corneal crosslinking and bandage contact lens use. J Cataract Refract Surg 2009;35:788e91. ↑ Kymionis GD, Portaliou DM, Bouzoukis DI, et al. Herpetic keratitis with iritis after corneal crosslinking with riboflavin and ultraviolet A for keratoconus. J Cataract Refract Surg 2007;33:1982e4. ↑ Kymionis GD, Bouzoukis DI, Diakonis VF, et al. Diffuse lamellar keratitis after corneal crosslinking in a affected person with post-laser in situ keratomileusis corneal ectasia. J Cataract Refract Surg 2007;33:2135e7.